Inflammation Plays an Unsuspected Role in Knee OA Pain

Janis C. Kelly

December 09, 2015

Knee osteoarthritis (OA) should no longer be thought of as a "noninflammatory" condition, as inflammation associated with synovitis or effusion plays a bigger role in worsening OA pain than mechanical load, according to a new report from the Multicenter Osteoarthritis Study (MOST), published online November 10 in Arthritis & Rheumatology.

The key finding was that there is an association between baseline presence of synovitis or effusion and pain threshold 2 years later (a marker of central pain sensitization), but not between baseline presence of bone marrow lesions (BMLs; a marker of mechanical load) and pain, lead author Tuhina Neogi, MD, PhD, told Medscape Medical News.

Dr Neogi, who is from the Clinical Epidemiology Unit, Boston University School of Medicine, Massachusetts, said, "These findings add to the growing understanding that there are different mechanisms by which pain can occur in knee OA, and further, that different pathologic structures can contribute to pain through different mechanisms."

Although the findings are not expected to affect current clinical practice, they do suggest that early targeting of inflammation might reduce sensitization (which contributes to a more severe pain experience in OA). Preventing the altered neurologic processing of nociceptive signals that usually occurs in OA might also prevent the progressive worsening of pain in knee OA.

Rheumatologist Kelly Weselman, MD, who was not involved in the study, told Medscape Medical News, "There are increasing data to suggest that OA is not just a wear-and-tear process. This study supports the idea that there is an inflammatory component to OA and the associated pain, rather than pain solely being due to mechanical factors. The study is not designed to evaluate the underlying cause of the joint changes in OA but does support that more than only mechanical change [is] involved in the symptoms of pain." Dr Weselman is chair of the American College of Rheumatology Communications and Marketing Committee, Atlanta, Georgia.

Dr Neogi and colleagues examined pain sensitization in 1111 subjects from the MOST study, a cohort of 3026 community-based subjects, aged 50 to 79 years, who had (one third) or were at risk for (two thirds) knee OA. At baseline, 21% of subjects reported frequent knee pain. The MOST study was funded by the National Institutes of Health.

All of the MOST study subjects had knee radiographs, knee magnetic resonance imaging scans, and standardized quantitative sensory testing (including temporal summation and pressure pain threshold [PPT]). Quantitative sensory testing was done at the wrist and patellae at baseline and 2 years later. The PPT, a measure of sensitivity to pain triggered by mechanical stimulation, was measured using pressure algometry at the affected knee and at the wrist (assumed to be a normal site). The researchers examined the relation of temporal summation and PPT to synovitis, effusion, and BMLs.

This report included 60-month and 84-month study visits, the first at which measures of sensitization were obtained. For the analysis, the 60-month visit was considered the baseline, and the 84-month visit was considered the follow-up. Analyses were adjusted for potential confounding by age, sex, body mass index, race, study site, radiographic OA severity (Kellgren and Lawrence grade for the tibiofemoral joint; presence of patellofemoral OA), depressive symptoms, catastrophizing, widespread pain using a validated standard homunculus, and analgesic use.

The cross-sectional and longitudinal analyses showed that synovitis was associated with greater pain sensitivity at the patella. Effusion was associated with greater pain sensitivity at the wrist and with risk for incident temporal summation. BMLs were not associated with either change in pain sensitivity.

The BML data were unexpected. Dr Neogi told Medscape Medical News. "I was surprised that we found no relation of bone marrow lesions to pain sensitization because one of our hypotheses, based on animal models, is that mechanical and/or inflammatory lesions can lead to sensitization. [BMLs] are thought to be largely a mechanically driven lesion, with some potential inflammatory component, and therefore would be a lesion of interest for this particular mechanism. This finding doesn't raise new questions per se, but rather suggests that we still need a better understanding of pain mechanisms in knee OA."

Questions remain about whether the changes in sensitization identified by Dr Neogi and colleagues actually mediate OA pain, are a consequence of synovitis-induced pain, or are a clinically insignificant incidental finding. Synovitis might directly alter central pain processing or might be just a marker for a subgroup more likely to undergo sensitization.

"There is some suggestion, though, that sensitization may in fact be influenced by genetic predisposition with generalized lower pain thresholds that may become manifest once nociceptive input from the osteoarthritic joint is received," the researchers point out.

An unexplained anomaly in the MOST subjects was that persistence of synovitis and effusions was associated with increased pain sensitivity, but resolution of those features on MRI was not associated with a significant improvement in PPT. The authors suspect that once sensitization has occurred, just cooling the inflammation might not be enough to correct it.

However, in an accompanying editorial, David A. Walsh, MD, from the Arthritis UK Pain Centre, City Hospital, Nottingham, United Kingdom, notes that earlier work by some of these researchers showed that arthroplasty was associated with reductions in sensitization. The joint prosthesis shields subchondral bone but leaves the synovium intact, which suggests osteochondral factors might play an important role in pain sensitization in OA.

Dr Walsh writes that synovitis, which is strongly associated with more severe OA, was present in only 38% of the MOST subjects at baseline, and that OA stage might have influenced the study outcomes.

"Lack of associated [sensitization] improvements in the MOST cohort [after resolution of synovitis and effusion on magnetic resonance imaging] might reflect limited statistical power, or imaging changes might not adequately reflect the molecular or cellular mechanisms that mediate the augmentation of neuronal sensitisation by synovitis," he adds. "More detailed study of pain mechanisms in randomised controlled trials of anti-inflammatory strategies in OA should determine whether improving synovitis can reduce neuronal sensitisation."

Dr Weselman commented, "The data are intriguing and raise some interesting questions. This article suggests some new areas that will require further research. It does appear that ongoing joint inflammation affects long-term pain sensitivity. This study supports the fact that earlier and more aggressive treatment of inflammation in OA may decrease long-term pain. The Implications are that we need to prevent synovitis and effusion to prevent increased pain sensitization. Once that process has started, we should target pain processing pathways, as we have already started doing."

The authors, Dr Walsh, and Dr Weselman have disclosed no relevant financial relationships.

Arthritis Rheum. Published online November 10, 2015. Article abstract


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